Merlin/NF2 regulates SLC7A11/xCT expression and cell viability under glucose deprivation at high cell density in
Itsuki Yamaguchi1,2, Hironori Katoh2
1Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Abstract:
The cystine/glutamate transporter SLC7A11/xCT is highly expressed in many cancer cells and plays an important role in antioxidant activity by supplying cysteine for glutathione synthesis. Under glucose-depleted conditions, however, SLC7A11-mediated cystine uptake causes oxidative stress and cell death called disulfidptosis, a new form of cell death. We previously reported that high cell density (HD) promotes lysosomal degradation of SLC7A11 in glioblastoma cells, allowing them to survive under glucose-depleted conditions. In this study, we found that the neurofibromatosis type 2 gene, Merlin/NF2 is a key regulator of SLC7A11 in glioblastoma cells at HD. Deletion of Merlin increased SLC7A11 protein level and cystine uptake at HD, leading to promotion of cell death under glucose deprivation. Furthermore, HD significantly decreased SLC7A11 mRNA level, which was restored by Merlin deletion. This study suggests that Merlin suppresses glucose deprivation-induced cell death by downregulating SLC7A11 expression in glioblastoma cells at HD.
Insights
Neurofibromatosis type 2 (NF2) protein Merlin suppresses cancer cell death under glucose deprivation. Merlin achieves this by downregulating the cystine/glutamate transporter SLC7A11, preventing oxidative stress in glioblastoma cells at high density.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- The cystine/glutamate transporter SLC7A11/xCT is crucial for antioxidant defense in cancer cells via glutathione synthesis.
- Glucose deprivation induces oxidative stress and a novel cell death pathway, disulfidptosis, mediated by SLC7A11.
- High cell density (HD) normally promotes glioblastoma cell survival under glucose-depleted conditions by degrading SLC7A11.
Purpose of the Study:
- To investigate the role of Merlin/NF2 in regulating SLC7A11 expression and glioblastoma cell survival under glucose-depleted conditions at high cell density.
- To elucidate the molecular mechanisms by which Merlin influences SLC7A11 activity and cell fate.
Main Methods:
- Utilized glioblastoma cell models with and without Merlin/NF2.
- Assessed SLC7A11 protein and mRNA levels under varying glucose conditions and cell densities.
- Quantified cystine uptake and cell death rates.
Main Results:
- Merlin/NF2 deletion significantly increased SLC7A11 protein levels and cystine uptake in glioblastoma cells at high cell density.
- Merlin deletion promoted cell death under glucose deprivation, contrary to the protective effect observed in wild-type cells.
- High cell density led to decreased SLC7A11 mRNA levels, an effect reversed by Merlin deletion.
Conclusions:
- Merlin/NF2 acts as a key suppressor of glucose deprivation-induced cell death in glioblastoma cells at high cell density.
- Merlin downregulates SLC7A11 expression, thereby mitigating oxidative stress and preventing disulfidptosis.
- Targeting the Merlin-SLC7A11 axis may offer therapeutic strategies for glioblastoma under specific metabolic conditions.
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